High-fat diet, muscular lipotoxicity and insulin resistance

High-fat diet, muscular lipotoxicity and insulin resistance

A high dietary fat intake and low physical activity characterize the current Western lifestyle.  Dietary fatty acids do not stimulate their own oxidation and a surplus of fat is stored in white adipose tissue, liver, heart and muscle. In these organs intracellular lipids serve as a rapidly available energy source during, for example, physical activity. However, under conditions of elevated plasma fatty acid levels and high dietary fat intake, conditions implicated in the development of modern diseases such as obesity and type 2 diabetes mellitus, fat accumulation in liver and muscle (intramyocellular lipids; IMCL) is associated with the development of insulin resistance. Recent data suggest that IMCL are specifically harmful when combined with reduced mitochondrial function, both conditions that characterize type 2 diabetes. In the (pre)diabetic state reduced expression of the transcription factor PPARg co-activator-1a (PGC-1a), which is involved in mitochondrial biogenesis, has been suggested to underlie the reduced mitochondrial function. Importantly, the reduction in PGC-1a may be a result of low physical activity, consumption of high-fat diets and high plasma fatty acid levels. Mitochondrial function can also be impaired as a result of enhanced mitochondrial damage by reactive oxygen species. Fatty acids in the vicinity of mitochondria are particularly prone to lipid peroxidation. In turn, lipid peroxides can induce oxidative damage to mitochondrial RNA, DNA and proteins. The mitochondrial protein uncoupling protein 3, which is induced under high-fat conditions, may serve to protect mitochondria against lipid-induced oxidative damage, but is reduced in the prediabetic state. Thus, muscular lipotoxicity may impair mitochondrial function and may be central to insulin resistance and type 2 diabetes mellitus.

Caveat:  This is a summary paper on how fats in the Western Diet "behave".  However even on a zero carb diet, our metabolic pathways, receptors and such do not change.   VLC diets switch us to an "alternate metabolism" based more on lipid oxidation by skeletal muscles.  In that context, UP3 should be upregulated and there shouldn't be "idle" fatty acids lying around to be prone to peroxidation.  There is, however, a rationale for a low fat diet and exercise approach to reversing the condition.

Obesity, energy balance and fat balance

By definition, the development of obesity and overweight is characterized by a positive energy balance. Numerous investigations (Schutz et al. 1989; Bennett et al. 1992) have shown that in the long term an imbalance between energy intake and energy expenditure is reflected in a positive fat balance. ... In addition, in human subjects there is evidence for a clear substrate hierarchy for the utilization of macronutrients, in which fat balance is least regulated. For example, the human body responds only very slowly by increasing fat oxidation when fat intake is increased (Thomas et al. 1992; Schrauwen et al. 1997a), leading to a deposition of dietary fat in the fat stores. On the other hand, the storage capacity for carbohydrate and protein in the human body is limited and therefore carbohydrate and protein oxidation are very well and rapidly adjusted to their respective intake (Abbott et al. 1988). As a consequence, a positive energy balance will be reflected in a positive fat balance.

This is a nice summary of the nutrient heirarchy and, although we can clearly consume excess calories on a low fat diet, it would require excessive carbohydrate consumption in positive caloric balance.

Fat oxidation on a high-fat diet

Although there is ample evidence that the adaptation of fat oxidation to increased fat intake is slow in man, the reason for this slow adaptation is relatively unknown. According to the two-compartment model of Flatt (1987), whole-body fat oxidation can be increased via an expansion of fat mass, leading to increased plasma NEFA levels available for oxidation. In this model the body is divided into two compartments, fat mass and glycogen stores, and the oxidation mixture of fatty acids and glucose depends on the size of these two compartments. As the glycogen stores are very limited in size, small changes in the size of the glycogen stores will affect glucose oxidation. In contrast, as the fat mass can be relatively unlimited in size, a large expansion of fat mass is needed before changes in fat oxidation will occur. This model can explain why the addition of a surplus of fat to a single meal, which will not result in a change in fat mass, does not affect fatty acid oxidation rates, and why obese subjects have relatively high fat oxidation. In fact, expansion of fat mass (obesity) could be considered as an adaptation of the body to increase fat oxidation to a level that matches a high dietary fat intake. 

This is interesting to me and makes sense.  It would not surprise me to find leptin controlling this.  I highlighted, however one statement that is often presumed opposite in nutritional circles of all stripe, LC in particular.  It turns out that the obese tend to "burn fat" just fine and fatty acids are available for the burning regardless of diet.

However, it has been shown (Schrauwen et al.1997a) that healthy human volunteers who consume a high-fat diet for 7 d, while being in energy balance, are able to slowly increase their fat oxidation to a level that equals the high-fat intake. As no substantial expansion of fat mass can be expected after 7 d of a high-fat diet, these results seem to contradict Flatt’s (1987) model. These findings have, however, been explained in terms of the changes in glycogen stores that may have occurred (Schrauwen et al. 1997b, 1998). During the first days on a high-fat diet, when fat oxidation does not equal fat intake, subjects are in negative carbohydrate balance (carbohydrate oxidation>carbohydrate intake), leading to a decrease in the body’s glycogen stores. According to Flatt’s (1987) two-compartment model, a decrease in glycogen stores would result in a decrease in glucose oxidation and would therefore be another way to increase fat oxidation.  Indeed, it has been shown (Schrauwen et al. 1997b, 1998) that lowering glycogen stores by exhaustive exercise markedly improves the rate at which subjects are able to adapt their fat oxidation to an increased fat intake.

In order to further investigate the mechanisms by which fat oxidation increases on a high-fat diet, a more detailed determination of fatty acid oxidation has been conducted in subjects consuming high-fat diets (Schrauwen et al. 2000). Interestingly, it was observed that the increase in fat oxidation after 7 d of a high-fat diet is completely accounted for by an increase in TAG-derived fatty acid oxidation {...}  mainly intramyocellular lipids (IMCL)) {and not plasma fatty acids). IMCL are small lipid droplets that are located in the sarcoplasm and predominantly found in the vicinity of mitochondria, suggesting that they may serve as a rapidly available energy source for the muscle. {...}it has recently been shown (Schrauwen-Hinderling et al. 2005) that the amount of IMCL is already markedly increased after 7 d of a high-fat diet in healthy lean subjects. {...} these combined observations of an increased IMCL mass and increased IMCL oxidation indicate that increases in IMCL content are also needed to drive increased IMCL oxidation. Thus, the slow rate at which fat oxidation adapts to increased fat intake when a high-fat diet is consumed may also be attributed to the time needed to increase IMCL content. {...}  Interestingly, it has been found (Schrauwen et al. 2002c) that when sedentary middle-aged subjects follow an endurance training programme for 3 months whole-body fat oxidation increases, and again this increase is completely accounted for by an increase in TAG-derived fatty acid oxidation. In accordance with the earlier mentioned hypothesis, endurance training is also known to increase IMCL content (Goodpaster et al. 2001; Schrauwen-Hinderling et al. 2006a), suggesting that similar mechanisms may be involved in the training- and diet-induced increase in fat oxidation.

So even in the presence of carbohydrates, our bodies adapt our substrate oxidation rates to our macronutrient intake.  Those consuming more fat will burn more fat provided it is an energy balanced diet.  It is net caloric excesses that throw things out of whack, and it would seem that most Western diets contain an excess of both fat and carbs.

OK, so what of IMCL and lipotoxicity?  Lipotoxicity is a term used to describe various detrimental effects of accumulated lipid in tissues not intended for storage.  The most toxic effect of which may be apoptosis -- cell death.

IMCL and IR

Evidence gathered in recent decades has pointed towards an important causal role of disturbed fatty acid metabolism in the development of type 2 diabetes mellitus. Not only are plasma glucose levels increased in uncontrolled type 2 diabetes, but also plasma NEFA, and the storage of fatty acids in non-adipose tissues such as pancreas, liver and muscle is elevated in patients with type 2 diabetes (Schalch & Kipnis, 1965). Moreover, a strong negative correlation has been found between the level of IMCL and insulin sensitivity in non-trained subjects (Perseghin et al. 1999), and levels of IMCL are increased in first-degree relatives of patients with type 2 diabetes who are insulin resistant, but not diabetic (Jacob et al. 1999). These data suggest that IMCL accumulation may be a primary factor in the development of type 2 diabetes.

The highlighted part is my cause for concern as this also occurs in the "pre diabetic" insulin resistant state.  In self-treating T2 -- especially if one is in early stages and hyperinsulinemic (IOW they can still make plenty of insulin -- is a low carb/high fat diet harmful but the the effects masked by the improved BG control?  There are two issues here:  1. Elevated NEFA and direct effects on circulatory system, etc. and 2. IMCL -- I think the question here is will IMCL "accumulate" in a VLC fat burner.  I've posted a lot of info (and more to come) on the plasma NEFA.  

The article goes on to present data on the impact and fates of IMCL.  IMCL is a source of energy -- readily available fatty acids.  But if there are too many and they are not burnt for energy, they are stored as triglycerides (TAG) in the muscle (or organ) cells instead of in the adipose tissue.  It is under these conditions that IMCL's cause deleterious effects.

I'm pretty much convinced that a high fat diet induces insulin resistance.  The question remains if this IR is relevant to low carbers who don't rely on a postprandial insulin response to clear glucose from the blood.  I have two thoughts on this as well:  1.  What of protein transport?   and 2.  What of those who do not adhere strictly to low carb?  Is something like the LoBAG diet (50% fat / 30% protein / 20% carbs) better if it can be adhered to more consistently?  It is still high fat, but there should be enough carbs in this diet to get NEFA under control once a modest weight loss has been achieved.

It seems to me that if someone becomes insulin resistant, the goal should be to reverse that IR, not merely mask the effect.  Here is where I have questions about VLC (that necessarily becomes high fat) diets for the long term.  More importantly, I think there's a lesson to be learned about EXERCISE -- something many in the LC community seem to have an aversion too.  In the article it is stated that T2's have impaired lipid oxidation capability -- dysfunctional mitochondria.  This seems to be due to expression of PGC-1alpha.  But this can be upregulated by both acute exercise and endurance training.  As the discussion states, the reduced expression seen in healthy relatives of T2's might tempt one to believe this is totally genetic, but this would not explain the rise in T2 and the earlier onset we are now seeing.  They postulate that reduced activity could play a role.  Of course that is speculation, but, especially in children, I see a lot less acute activity going on.  It would also seem that on a LC diet, exercise might even be MORE important than on a low fat calorie restricted diet!

A role for oxidative stress in the development of insulin resistance

Since the finding that mitochondrial function may be impaired in the (pre)diabetic state, most studies have focused on PGC-1a and mitochondrial biogenesis. However, mitochondrial function is not only determined by mitochondrial biogenesis, but also by mitochondrial quality. In the latter context, it has been shown (Kelley et al. 2002) that mitochondria from patients with type 2 diabetes are smaller and show morphological abberations when compared with controls, and mitochondrial area correlates positively with insulin sensitivity. The smaller and damaged mitochondria in skeletal muscle of patients with diabetes also result in an impaired functional capacity (Kelley et al. 2002). Thus, mitochondria of patients with type 2 diabetes have a reduced electron transport chain capacity{...}

To explain the observed mitochondrial damage, elevated production of reactive oxygen species (ROS) and its by-products (e.g. lipid peroxides) has been suggested. In addition to the production of ATP, mitochondria are also the major contributor to the production of ROS. Mitochondrial ROS can react rapidly with DNA, protein and lipids, thereby leading to so-called oxidative damage.  Recent evidence points towards a causal role for ROS in the development of insulin resistance. {...}

Fatty acids are especially very prone to ROS-induced oxidative damage, resulting in the formation of lipid peroxides, which in turn can induce damage to proteins and DNA. Thus, accumulation of fatty acids in the vicinity of the mitochondrial matrix, where ROS are formed, increases the likelihood of lipid peroxidation. As discussed earlier, patients with type 2 diabetes are characterized by the accumulation of IMCL and these lipid droplets are located close to the mitochondria. To prevent simple diffusion of fatty acids into the mitochondria their entry is regulated{...} however, this system cannot completely prevent the diffusion of fatty acid into the mitochondria. {...}  It can easily be imagined that this ‘passive diffusion’ is more likely to occur under conditions of a high IMCL concentration{...}  Consistent with this notion, skeletal muscle of subjects who are obese and insulin resistant not only contains a higher amount of IMCL, but these lipids also show a higher extent of lipid peroxidation (Russell et al. 2003b). Potentially, these lipid peroxides could lead to oxidative damage to mitochondrial structures and explain the increased mitochondrial damage observed in patients with type 2 diabetes (Kelley et al. 2002).

This is sobering food for thought.

The article goes on to discuss UCP3 - Uncoupling Protein 3 in the mitochondria.  This protein seems to be involved in transporting LCFA's that are not oxidized out of the mitochondria so that they don't undergo lipid peroxidation and do damage.  This is a theory but one that seems to agree with the evidence presented.  UCP3 is suppressed in pre(diabetics) but lifestyle intervention and/or an endurance training program restore this to normal levels.